Is RELN p.Ser2725Phe (c.8174C>T) pathogenic?

RELN p.Ser2725Phe (c.8174C>T) is classified Likely benign in RELN (ClinVar, Single submitter, 3 submitters; last evaluated 2025-11-09). AlphaMissense: likely benign (0.3036); Ultra-rare (popmax 0.0319%, sas); Associated with Norman-Roberts syndrome.

What condition is associated with RELN p.Ser2725Phe (c.8174C>T)?

RELN p.Ser2725Phe (c.8174C>T) is associated with Norman-Roberts syndrome, familial temporal lobe epilepsy 7 (ClinVar).

How common is RELN p.Ser2725Phe (c.8174C>T) in the general population?

RELN p.Ser2725Phe (c.8174C>T) is ultra-rare (popmax 0.0319%, sas) (gnomAD).

What do computational predictors say about RELN p.Ser2725Phe (c.8174C>T)?

AlphaMissense predicts likely benign (score 0.3036) — an in-silico prediction, not a clinical call.

RELN p.Ser2725Phe

c.8174C>T · rs138975709 · VCV1001230

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3036 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0319%, sas)

Conditions

Norman-Roberts syndrome

Computational evidence

Protein change
AlphaMissense	0.3036	likely benign
REVEL	0.424	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 67 kb · p 2.1e-16 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0319% South Asian · 29/91,044 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.0031% 50/1,612,968 alleles · ultra-rare exomes 45/1,460,722 · genomes 5/152,246 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0319%	3,139
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.0017%	58,952

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RELN
Protein: p.Ser2725Phe
Coding: c.8174C>T
MANE Select: NM_005045
dbSNP: rs138975709
Type: single nucleotide variant
Location: chr7:103510951 (GRCh38)
Gene constraint: LOEUF 0.276 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)

Full RELN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Norman-Roberts syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial temporal lobe epilepsy 7

Similar variants

RELN c.3912+2T>G Likely pathogenic ★★ same condition
RELN c.7349+2T>C Likely pathogenic ★★ same condition
RELN p.Arg1622Ter Pathogenic/Likely pathogenic ★★ same condition
RELN c.1893-3C>T Uncertain significance ★★ same condition
RELN c.227-3C>T Uncertain significance ★★ same condition
RELN c.2465+5G>T Uncertain significance ★★ same condition
RELN c.6072+3A>G Uncertain significance ★★ same condition
RELN c.6072+4C>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/reln-p-ser2725phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown